Dr. Pashmforoush is a highly trained clinician and scientist with training in molecular biology and clinical cardiology. The purpose of this grant proposal is to obtain support to enable Dr. Pashmforoush to become an independent investigator by the end of the proposed funding period. The proposed research will be performed in the laboratory of Dr. Kenneth Chien in the Institute of Molecular Medicine at the University of California, San Diego. During this time, Dr. Pashmforoush will receive the necessary training for electrophysiologic methodology to apply to murine models of human conduction system disease. UCSD and specifically, Dr. Chien's laboratory in the IMM will provide an ideal environment that has been extraordinarily successful for promoting and developing similar research interests. The long-term goals of this project are to study the mechanisms of human conduction system disease by using animal models. In this regard, cardiac arrhythmias remain important causes of cardiovascular morbidity mortality worldwide. Mutations in gene encoding the homeobox transcription factor NKX 2.5 are found to cause a non-syndromic human congenital heart disease with progressive conduction system disease leading to complete heart block. Following these observations, our hypothesis is that NKX 2.5 plays a critical role in the developmental maturation and maintenance of the cardiac conduction system and in particular the AV node. In the current proposal we will utilize a mouse model system to gain insight into the mechanistic pathways that link defects in the pattern of expression of NKX 2.5 with the associated cardiac arrhythmia. Similar to observations made in families with heart block, mice deficient for NKX 2.5 develop progressive AV nodal degeneration leading to complete heart block. Accordingly, our Specific Aims in this proposal are: To determine the role of NKX 2.5 in the development, maturation and maintenance of AV node and the distal conduction system. To define the role of NKX 2.5 in the development and maintenance of the atrial conduction system including the SA node, and to assess the postnatal requirement for the NKX 2.5 in the maintenance of the cardiac conduction system including the SA node, AV node, and the HIS-Purkinje system. We now have all the necessary tools to successfully accomplish the specific aims of this project.